NM_001323289.2:c.283-43G>A

Variant names:

• chrX-18579805-G-A
• rs267608448
• NM_001323289.2:c.283-43G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001323289.2(CDKL5):​c.283-43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,161,061 control chromosomes in the GnomAD database, including 2 homozygotes. There are 261 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., 17 hem., cov: 23)
  • Exomes 𝑓: 0.00072 (2 hom. 244 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 0.868

Genes affected

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-18579805-G-A is Benign according to our data. Variant chrX-18579805-G-A is described in ClinVar as [Benign]. Clinvar id is 156084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000595 (66/110918) while in subpopulation NFE AF= 0.001 (53/52864). AF 95% confidence interval is 0.000787. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.283-43G>A		intron_variant	Intron 5 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.283-43G>A		intron_variant	Intron 6 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.283-43G>A		intron_variant	Intron 5 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.283-43G>A		intron_variant	Intron 5 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.000595 AC: 66 AN: 110875 Hom.: 0 Cov.: 23 AF XY: 0.000513 AC XY: 17 AN XY: 33165

Gnomad AFR AF: 0.000229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000193

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.000757

Gnomad FIN AF: 0.000172

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000594 AC: 108 AN: 181815 Hom.: 1 AF XY: 0.000642 AC XY: 43 AN XY: 67007

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000735

Gnomad ASJ exome AF: 0.000805

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00122

Gnomad FIN exome AF: 0.0000630

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000719 AC: 755 AN: 1050143 Hom.: 2 Cov.: 22 AF XY: 0.000750 AC XY: 244 AN XY: 325411

Gnomad4 AFR exome AF: 0.000472

Gnomad4 AMR exome AF: 0.0000571

Gnomad4 ASJ exome AF: 0.000897

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.000223

Gnomad4 NFE exome AF: 0.000799

Gnomad4 OTH exome AF: 0.000473

GnomAD4 genome AF: 0.000595 AC: 66 AN: 110918 Hom.: 0 Cov.: 23 AF XY: 0.000512 AC XY: 17 AN XY: 33218

Gnomad4 AFR AF: 0.000229

Gnomad4 AMR AF: 0.000192

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.000760

Gnomad4 FIN AF: 0.000172

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00105 Hom.: 6

Bravo AF: 0.000548

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 13, 2014

RettBASE

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

Unlikely to be pathogenic, not predicted to change splicing; however, there is no empirical evidence for this -

CDKL5 disorder Benign:1

Jul 12, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v4 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

not provided Other:1

-

RettBASE

Significance: not provided

Review Status: flagged submission

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267608448; hg19: chrX-18597925;